Sulfur derivatives of pyrazolo (3,4-b)pyridines

ABSTRACT

NEW SULFUR DERIVATIVES OF PYRAZOLO(3,4-B)PYRIDINES HAVING THE GENERAL FORMULA   1-R1,3-R2,4-(R3-S(=O)N-),5-(R4-CO-),6-R5-1H-PYRAZOLO(3,4-   B)PYRIDINE   AND ALSO THEIR SALTS, ARE USEFUL AS CENTRAL NERVOUS SYSTEM DEPRESSANTS. THESE COMPOUNDS ALSO INCREASE THE INTRACELLULAR CONCENTRATION OF ADENOSINE-3&#39;&#39;,5-CYCLIC MONOPHOSPHATE.

United States Patent US. Cl; 260-294.8 C 8 Claims ABSTRACT on THE DISCLOSURE New sulfur derivatives 'of pyrazolo[3,4-b]pyridines having the general formula and also their salts, are useful as central nervous system depressants. These compounds also increase the intracellular concentration of adenosineSQS-cyclic monophosphate.

SUMMARY OF THE INVENTION This invention relates to new pyrazo1o[3,4-b]pyridines, and salts thereof. These new compounds have the general formula The symbols have the following meanings in Formula I and throughout this specification: R represents hydro gen, lower alkyl, phenyl, phenyl-lower alkyl or cyclolower alkyl, R represents hydrogen, lower alkyl or phenly, R represents hydrogen (only when n is 0) lower alkyl, phenyl, phenyl-lower alkyl or a nitrogen heterocyclic, R repersents hydroxy, lower alkoxy, lower alkyl, phenyl or an acyclic or heterocyclic amine radical. R represents hydrogen, lower alkyl or phenyl. n is 0, l or 2.

Preferred compounds of Formula I are those in which R, is hydrogen or lower alkyl, especially ethyl, R is hydrogen or methyl, R is hydrogen or lower alkyl, especially methyl or ethyl, phenyl or heterocyclic, especially imidazole, n is 0 or two, R is hydroxy, lower alkoxy, especially ethoxy, lower alkyl especially, methyl, phenyl or lower-alkylamino, R is hydrogen or methyl.

DETAILED DESCRIPTION OF THE INVENTION The various groups referred to above are of the following types: the lower alkyl groups include straight or branched chain hydrocarbon groups of up to 7 carbon atoms like methyhethyl, propyl, isopropyl, butyl, amyl,

3,773,778 Patented Nov. 20, 1973 hexyl and the like, methyl, ethyl, propyl and butyl being preferred. The lower alkoxy-groups and hydroxy-lower alkyl groups (referred to below) similarly include such alkyl groups linked to an oxygen atom or hydroxy group, respectively, e.g., methoxy, propoxy, ethoxy, isopropoxy, hydroxymethyl, hydroxyethyl and the like. The cycloalkyl groups are 3- to fi-carbon alicyclics including cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the last two being preferred. a

The nitrogen heterocyclics represented by R are 5- or 6-membered monocyclic nitrogen heterocyclics in which there are (exclusive of hydrogen) one or two nitrogen atoms, one nitrogen atom and one sulfur or one oxygen atom, the remaining being carbon. These include, for example, imidazolyl (which is preferred), piperidyl, pyrrolidyl, morpholinyl, thiamorpholinyl, or piperazinyl. These heterocyclics may also bear a lower alkyl, lower alkoxy or hydroxy-lower alkyl group.

R may form an amide radical with the carbonyl group. In this instance R represents the basic nitrogen containing radical in which, R, and R each represents hydrogen, lower alkyl or hydroxy-lower alkyl forming such basic groups as amino, lower alkylamino, e.g., methylamino, ethylamino, isopropylamino, di(lower alkyl)amino, e.g., dimethylamino, diethylamino, dipropylamino, (hydroxy-lower alkyl)amino, e.g., hydroxyethylamino, di(hydroxy-lower alkyl)amino, e.g., di(hydroxyethyDamino.

In addition the nitrogen may join with the groups represented by R and R to form a 5- or 6-membered monocyclic heterocyclic similar to those described above, containing, if desired, an oxygen, sulfur or an additional nitrogen atom, (not more than two hetero atoms altogether) e.g., piperidino, pyrrolidino, morpholino, thiamorpholino or piperazino. These heterocyclic groups may also bear a lower alkyl, lower alkoxy or hydroxy-lower alkyl group.

Representative heterocyclic groups include, for example, piperidino, 2-, 3- or 4-(lower alkoxy)piperidino, e.g., 2-methoxypiperidino, 2-, 3- or 4-(lower alkyl)piperidino, e.g., 2-, 3- or 4-methylpiperidino, pyrrolidino, (lower alkyl)pyrrolidino, e.g., 2-methylpyrrolidino, (lower alkoxy) pyrrolidino, e.g., 2-ethoxypyrrolidino, lower alkyl pyrrolidino, e.g., 2-methylpyrrolidino, morpholino, (lower alkyl) morpholino, e.g., 3-methylmorpholino or Z-methylmorpholino, (lower alkoxy)morpholino, e.g., Z-ethoxymorpholino, thiamorpholino, (lower alkyl)thiamorpholino,

e.g., 3-methylthiamorpholino or Z-methylthiamorpholino, (lower alkoxy)thiamorpholino, e.g., 2-methoxythiamorpholino, piperazino, (lower alkyl) piperazino, e.g., 4- imetliylpiperazino, 2-methylpiperazino or (hydroxy-lower alkyl)piperazino, e.g., 4-(2-hydroxyethyl)piperazino.

The new compounds of Formula I are formed by the following series of reactions. The symbols in the structural formulas have the same meaning as previously de scribed.

To produce a compound of Formula I wherein R is other than hydrogen and R is hydroxy, lower alkoxy, lower alkyl or phenyl, a S-aminopyrazole of the formula L 1 J-NH:

[produced analogous to the procedure, described in Z. f. Chemie 10 386 (1970)] is made to react with a compound of the formula alkyl-O- 0 0 O-alkyl COR;

by heating at a temperature of about l20-130 C.

The resulting compound of formula C O 0 -alkyl R:

(V) C 0 R4 is cyclized in an inert organic solvent such as diphenyl ether at about 230 to about 260 C. while distilling off the alcohol formed, producing a compound of formula This 4-hydroxy compound is refluxed for several hours with a phosphorous halide like phosphorous oxychloride to obtain the intermediate of formula 0 RT I -Ra N N RI wherein X is chlorine or bromine.

Alternatively, instead of cyclizing the compound of Formula V in an inert organic solvent at about 230 to 260 as described above, this product also undergoes cyclizationby treatment with a phosphorous halide like phosphorous oxychloride producing directly the intera mediate of Formula VII.

The products of Formula I are then prepared from compounds of Formula VII by reaction with a mercaptan of the formula I (VIII) R3-SH' In order to obtain sulfur compounds of Formula -I which n represents 1 or 2 an oxidationreaction 'hasto follow. This may be efiected with the foregoing product (IX) R:

K Rs

wherein R is lower alkoxy, is hydrolyzed, e.g., with aqueous sodium hydroxide, to obtain the corresponding compound wherein R is hydroxy. This is then processed, in a manner analogous to that described in the copending application of Hans Hoehnand Jack Bernstein, Ser. No. 195,808, filed Nov. 4, 1971, converting it by means of thionyl chloride or a phosphorous halide like the bromide or chloride to a compound of the formula l l i 0 0X N N R:

wherein X is chlorine or bromine. Reaction of a compound of Formula X with an amine of the formula (X Re HN I at room temperature or below in a hydrocarbon solvent like benzene provides the desired amide.

In order to obtain a product of Formula I wherein R is hydrogen a modification of the foregoing procedure is required. According to this modification, a S-aminopyrazole of Formula HI is used, wherein R is an arylmethyl group or a heteromethyl group. This starting material has the formula 1 wherein R is an'aromatic or heterocyclic nucleus like phenyl, naphthyl, furyl, pyridyl, pyrimidyl', pyrazinyl or the like. Furyl and pyridyl are preferred.

This starting material is processed as described above through the reaction .with a compound of Formula -IV and cyclization of theproduct corresponding to-Formula V to obtain a compound of Formula VI.

At this point, the compound-of Formula VI, having the CH -R substituent of Formula HIa in the 1- position, is oxidized with a 'metal'oxide oxidizing agent like selenium dioxide ina high boilng solvent lke diethyleneglycol dimethylether at about L60? C. yields a compound of Formula VI, wherein R -is hydrogen. Subsequently, this intermediate" is converted, as described above, to the 4-halo compoundof Formula VH by means of phosphorous oxychloride, which in turn is treated with the mercapto compound of Formula VIH and, oxidized or otherwise processed as described above.

The compounds of Formula I form salts which are also part of this invention. The salts include acid-addition salts, particularly the non-toxic, physiologically acceptable members. The bases of Formula I form salts by reaction with a variety of inorganic and organic acids providing acid addition salts including, for. example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate, toluenesulfonate and the like. The acid addition salts frequently provide a convenient means for isolating the product e.g., by forming and precipitating the salt in a medium in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of Formula I. Other salts may then be formed from the free base by reaction with an equivalent of acid.

- The new compounds of this invention are central nervous system depressants and maybe used as tranquilizers or ataractic agents for the reliefof anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species, in the same manner as chlorodiazepoxide. For this purpose a compound or mixture of compounds of Formula I or non-toxic, physiolgically acceptable acid addition salt thereof, may be administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of about 1 to 50 mg. per kilogram per day, is appropriate. These may be conventionally formulated in an oral or parenteral dosage form by compounding about to 250 mg. per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.

The new compounds also increase the intracellular concentration of adenosine-3',5'-monophosphate, and thus by the administration of about 1 to 100 mg./kg./day, preferably about 10 to 50 mg./kg., in single or two to four divided'doses, in conventional dosage forms such as those described above, may be used to alleviate the symptoms of asthma.

The following examples are illustrative of the invention and constitute preferred embodiments. All temperatures are on the centigrade scale.

EXAMPLE 1 1-ethyl-4-ethylmercapto- 1 H-pyrazolo 3,4-b pyridine-5- carboxylic acid ethyl ester 7 (a) [[(1 ethyl 5 pyrazolyl)amino]mcthylene] malonic acid diethyl ester.-245 g. of 1-ethyl-5-aminopyrazole (2.2 mol.) and 476 g. of ethoxymethylene malo- The compound is recrystallized from n-hexane, M.P. 55470. M

S-carboxylic acid and ethyl,ester.253 g'. of [[(1-ethyl-5-.

pyrazolyl)amino]methylene]malonic. acid diethyl ester (0.09 mol.) are dissolved in 770g. of diphenyl ether. The reaction mixture is heated to 235-250 (bath temperature) and allowed to react at this temperature for 1-2 hours while the resulting ethanol is continuously distilled oif. The last amount of alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1- ethyl-4-hydroxy-1H-pyrazolo[3,4b] pyridine 5 carboxylic acid ethyl ester is obtained at RR 115-120, yield 195 g.=92% of theory, M.P. -87". The compound is recrystallized from benzene to M.P. 87-89. Hydrolysis of this product with aqueous sodium hydroxide yields 1-ethyl-4-hydroxy 1H pyrazolo[3,4-b] pyridine-S-carboxylic acid, M.P. 201202.

(c) 4-chloro-1-ethyl-1H pyrazolo[3,4 b]pyridine 5- carboxylic acid ethyl ester.A mixture of 23.5 of l-ethyl- 4 hydroxy 1H pyrazolo[3,4 b] pyridine-S-carboxylic acid ethyl ester (0.1 mol.) and 150 ml. of phosphorous oxychloride is refluxed for 4 hours. Subsequently the excess phosphorous oxychloride is removed by means of vacuum distillation. As soon as the phosphorous oxychloride has been removed, the oily residue solidifies on cooling. It is treated with Water and filtered under suction (24.5- g.), M.P. 55-60". The 4-chloro-lethyl-1H-pyrazolo[3,4 b]pyridine 5 carboxylic acid ethyl ester is recrystallized from n-hexane (22.5 g. =87%), M.P. 62".

(d) 1-ethyl-4-ethylmercapto 1H pyrazolo[3,4 b] pyridine-S-(zarboxylic acid ethyl ester.-In a solution of 2.5 g. of ethylmercaptan (0.01 mol.) in 20 ml. of benzene, 0.25 g. of sodium (0.011 mol.) is introduced. The reaction mixture is stirred for 3 hours at room temperature and upon standing overnight 2.5 g. of 4-chloro-1-ethyll-l-ethyl-3-methyl-4- (methylsulfonyl)-lH-pyrazolo- [3,4-b]pyridine-5-carboxylic acid ethyl ester (a) [[(l-ethyl-3-methyl-5 pyrazolyl)amino]methylene]malonic acid diethyl ester.12.5 g. of 1-ethyl-3- methyl-S-aminopyrazole (0.1 mol.) and 21.6 g. of ethoxymethylene malonic acid diethyl ester (0.1) mol.) are heated to (bath temperature) for 2 hours with stirring. The ethanol formed by this reaction is removed by means of a water aspirator. Then vacuum distillation (B.P. M5 152-153") yields 24.0 g. (81.5% of theory) of a quickly crystallizing oil [[(l-ethyl-3-methyl 5 pyrazolyl)amino]methylene]malonic acid diethyl ester, M.P. 60-67. The product, recrystallized from benzene (90- 100), melts at 69-70".

(b) 1-ethyl-4-hydroxy 3 methyl-lH-pyrazolo[3,4-b] pyridine-S-carboxylic acid ethyl ester.'-14.8 g. of [[(1- ethyI-S-methyl 5 pyrazolyl)amino] methylene1-malonic acid diethyl ester (0.05 mol.) are dissolved in 50 g. of diphenyl ether. The reaction mixture is heated to 235- 250 (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while the resulting ethanol 7 is continuously distilled off. The last part of the alcohol is removed by means of a water, aspirator. The diphenyl ether is separated by' distillation with a fractionating 'column in vacuo. The 1-ethyl-4-hydroxy-3-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esteris obtained at B.P. 125-129, yield 10.7 g.=86% of theory, M.P. 91-93". The compound is recrystallized from benzene (90-100"), M.P. 93-94.

(c) 4-chloro 1 ethyl-3-methyl-1H-pyrazolo[3,4-b] pyridine-S-carboxylic acid ethyl ester.-By substituting an equivalent amount of 1 ethyl-4-hydroxy-3-methyl-1H- pyrazolo[3,4-b]pyridine-S-carboxylic acid ester for the 1- ethyl-4-hydroxy 1H pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester in the procedure of Example 1c, 4- chloro-1-ethyl-3-methyl 1H pyrazolo[3,4-b]pyridine-5- carboxylic acid ethyl ester, M.P. 78-80", is obtained.

(d) l-ethyl 3 methyl-4-(methylsulfonyl)-1H-pyrazolo[3,4 b]pyridine-5-carboxlic acid ethyl ester.By treating 10.6 g. of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo- [3,4-b]pyridine-S-carboxylic acid ethyl ester (0.04 mol.) with sodium methylmercaptan (0.044 mol.) in 75 ml. of absolute alcohol for five hours at room temperature and working up the product as in Example 1d, 1-ethyl-3- methyl-4-methylrnercapto 1H pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (6.8 g., oil) is obtained. After exposure to air, 5.9 g. of 1-ethyl-3-methyl-4-(methylsulfonyl)-1H-pyrazolo[3,4-b]pyridine 5 carboxylic acid ethyl ester are obtained, recrystallized from cyclohexane, M.P. 92-94.

EXAMPLE 3 1-ethyl-4-[(1-methyl-2-imidazolyl)thio]-lH-pyrazolo- [3,4-bJpyridine-S-carboxylic acid ethyl ester (a) 4-chloro 1 ethyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester.-A mixture of 12 g. of [[(1- ethyl-5-pyrazolyl) amino]-methylene]malonic acid diethyl ester (0.043 mol.) and 70 ml. of phosphorous oxychloride is refluxed for hours. Subsequently, the excess phosphorous oxychloride is removed in vacuo and the oily residue is treated with 50 ml. of water. The oil then becomes crystalline. The solid material is filtered under suction and dried in a desiccator, yield 8.5 g.=79% of theory. The 4-chloro 1 ethyl-1H-pyyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester is recrystallized from nhexane, M.P. 62.

(b) 1-ethyl-4-[(1-methyl 2 imidazolyl)thio]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid and ethyl ester.- In a solution of 2.5 g. of sodium (0.11 mol.) in 100 ml. of absolute ethanol, 11.5 g. of 2-mercapto-1-methylimidazole (0.1 mol.) are introduced and the whole is stirred for minutes. Then a solution of 25.3 g. of 4-chlorol-ethyl-lH-pyrazolo[3,4-b]pyridine 5 carboxylic acid ethyl ester in 50 ml. of absolute alcohol is added and the reaction mixture is heated for 3 hours at 50. Upon standing overnight, the precipitate is filtered under suction, washed with water in order to dissolve sodium chloride and then dried (19 g.). An additional 4 g. of 1-ethy1-4- [(l-ethyl 2 imidazolyl)thio]-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester is obtained by evaporating the mother liquor; total yield=69%, M.P. l44-146. The compound is recrystallized from alcohol, M.P. 145- 146.

33 g. of 1-ethyl-4-[(1-methyl-2-imidazolyl)thio]-1H- pyrazolo[3,4-b] pyridine 5 carboxylic acid ethyl ester (0.01 mol.), saponified by means of 40 ml. of 5% sodium hydroxide solution of 8 hours at room temperature, provides upon saponification and acidification of the solution with acetic acid 2.8 g. of 1-ethyl-4-[(1-methy1-2- imidazolyl)thio]-1H-pyrazolo[3,4 b]pyridine 5 carboxylic acid, M.P. 220-224, recrystallization from alcohol, M.P. ZZZ-224.

. EXAMPLE 4 I 1-ethyl-4-mercapto-lH-pyrazolo[3,4-b1pyridine-5- carboxylic acid ethyl ester By treating the 4 chloro-1-ethyl-1H-pyrazolo[3,4-b] pyridine-5-carboxylic acid ethyl ester of Example 3a with sodium hydrosulfide as in'lExample 2d, 1 ethyl-4-mercapto-1H-pyrazo1o[3,4-b]pyridine-S-carboxylic acid ethyl ester is obtained, M.P. 109110.

EXAMPLE 5 1-ethyl-4-phenylmercaptolH-pyrazolo 3,4-b pyridine- 5-carboxylic acid (a) l-ethyl-4-phenylmercapto-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester.-12.7 g. of 4-chlorol-ethyl-lH-pyrazolo[3,4-b1pyridine 5 carboxylic acid ethyl ester (0.05 mol.) are dissolved in 50 ml. of anhydrous alcohol and treated with 7.5 g. of potassium thiophenolate for 5 hours at After this time the precipitated potassium chloride is filtered 0E and the solvent removed in vacuo. The residue, recrystallized from hexane, yields 13.2 g. of 1-ethyl-4-phenylmercapto-lH-pyrazolo- [3,4 b]pyridine-5-carboxylic acid ethyl ester (80%), M.P. 68.

(b) l-ethyl 4 phenylmercapto-1H-pyrazolo[3,4-b] pyridine-S-carboxylic acid.-32.7 g. of 1-ethyl-4-phenylmercapto-1H-pyrazolo[3,4 b] pyridine-S-carboxylic acid ethyl ester (0.1 mol.) are treated with 10 g. of potassium hydroxide in ml. of alcohol for 12 hours at 60-70. The solvent is evaporated to dryness and the residue dissolved in 50 ml. of water. After acidifying the clear solution with acetic acid, 1-ethyl-4-phenylmercapto-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid precipitates and is filtered off. Recrystallization from acetic acid yields 25 g. (84%), M.P. 248.

EXAMPLE 6 1-ethyl-4-ethylmercaptolH-pyrazolo [3,4-b1pyridine- 5 -N-butylcarboxamide (a) l-ethyl 4 ethylmercapto-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acid-Hydrolysis of 1-ethyl-4-ethylmercapto-lH-pyrazolo[3,4b]pyridine-5-carboxylic acid ethyl ester from Example 1d with aqueous sodium hydroxide at room temperature and stirring yields after acidification 1-ethy1-4-ethylmercapto 1H pyrazolo[3,4-b]pyridine- S-carboxylic acid.

(b) l-ethyl 4 ethylmercapto-1H-pyrazolo[3,4-b]pyridine-S-carboxylic acid chloride-26.5 g. of 1-ethyl-4-ethylmercapto-lH-pyrazolofi3,4-b]pyridine-5-carboxylic acid and ml. of thionyl chloride are refluxed for 7 hours. Subsequently, the thionyl chloride is removed by means of a water aspirator. The residue, contains the crude 1- ethyl 4 ethylmercapto-lH-pyrazolo[3,4-b1pyridine-5- carboxylic acid chloride, which can be used without further purification for the reaction step. I r

(e) l-ethyl 4 ethylmercapto-lH-pyrazolo[3,4-b]pyridine-S-N-butylcarboxamide.To 7.5 g. of l-ethyl-4-ethylmercaptolH-pyrazolo [3,4-b]pyridine 5 carboxylic acid chloride suspended in 60 ml. of benzene are added slowly 4.4 g. of butylamine. After a short time the starting material dissolves and the solution becomes temporarily clear. Upon standing at room temperature for 24 hours, a precipitate forms which consists of butylamine hydrochloride as well as l-ethyl-4-ethylmercapto-lH-pyrazolo- [3,4-b]pyridine-S-N-butylcarboxamide. The precipitate is filtered under suction and washed with 'water in order to dissolve the butylamine hydrochloride. There remains 1- ethyl 4 ethylmercapto-lH-pyrazolo[3,4-b1pyridine-5- N-butylcarboxamide.

The following compounds are prepared by the procedure of Example 1, 2, 3 or 6 by substituting the appropriately substituted 4-chloro-lH-pyrazolo[3,4-d1pyridine-5- carboxylic acid ethyl ester, the appropriate mercaptan and 10 (d) 5-acetyl-4-butylmercapto 1 ethyl-lH-pyrazoloamine: [3,4-b]pyridine.11.2 g. of 5-acetyl-4-chloro-l-ethyl-pyr- R I CO-R4 N N I Example R Ra Ra 4 5 7 H H CHr-CH 0 -OC;H5 E 8 "Q E CHa-CHr- 2 0C:|H5 H 9 Q 0H3- CH- 2 -0C2Hi H CHr- 10.....'.'...'.'-.' CHa- GHQ-CH2- O OC:H5 H

11 CHPCHP H OHS-CH2 0 -oo,H, CH3- 1 3- CH3- CHr-(CH2)a 0 -0C2H5 CH;

13., CHr-CHg- CHa(CHz)z 2 OC2H5 H 14 0H3- 0113-- Q 1 0o,H, H

15.-.... CHr-(CHfir- H 2 -0O,H H

GHQ-

16-.-; CHr(CHz) CH3 CHr-CHP 0 -0C:H CH3- 17---.- CHPCHP H (OHa)zCH- 0 --0C:Hn Q

1s CHr-CHa- H CHPCHQ 0 --NH, 11 19 H CHa- C ix-( H2):- 0 -NHC4Hn Q 2o----.-.-.-..-- 01191011 H en's-0H, o -N o,H5 H 21 Q on.- cm 2 -N(c m 0H,

EXAMPLE 22 azolo[3,4-b]pyridine (0.05 mol.) are treated together 5-acetyl-4-butylmercapto-l-ethyl-lH-pyrazolo[3,4-b] pyridine (a) (l-ethyl 5 pyrazolyl)aminomethylene acetoacetic acid ethyl ester.-222 g. of l-ethyl-S-aminopyrazole (2 mol.) and 372 g. of ethoxymethyl'ene acetoacetic acid ethyl ester (2 mol.) are heated together at 120-l30, with stirring, until the theoretical amount of alcohol is distilled 01f. Cooling and recrystallization from methanol yields 375 g. of (l-ethyl-S-pyrazolyl)aminoethylene acetoacetic acid ethyl ester (75% M.P. 5355.

(b) S-acetyl 1 ethyl-4-hydroxy-lH-pyrazolo[3,4-b] pyridine-300 g. of (l-ethyl-S-pyrazolyl)aminomethylene acetoacetic acid ethyl ester (1.2 mol.) are placed into a flask which is heated in an oil bath for 5 minutes at 260 while the alcohol formed is distilled off. After this time, the flask is cooled as rapidly as possible. The residue is recrystallized from methanol and yields 148 g. of S-acetyl-lethyl 4 hydroxy-lH-pyrazolo[3,4-b1pyridine (60%), M.P. 155l57.

(c) S-acetyl 4 chloro-l-ethyl- 1H-pyrazolo[3,4-b] pyridine-20.5 g. of S-acetyl-1-ethyl-4-hydroxy-lH-pyrazolo[3,4-b]pyridine (0.1 mol.) are treated with ml. of phosphorus oxychloride at 60 for 12 hours. The excess of phosphorus oxychloride' is removed in vacuo and the residue is poured onto ice. 5-acetyl-4-chloro-l-ethyl-lH-pyrazolo[3,4-b]pyridine separates and is recrystallized from petroleum ether, yield 14.5 g.(65%), M.P. 55.

with a suspension of sodium butylmercaptide in anhydrous dioxane (prepared from 4.5 g. of butyl mercaptan and 1.2 g. of sodium hydride in 50 ml. dioxane) for 2 hours. After this time, sodium chloride separates and is filtered oil. The residue is evaporated to dryness, and recrystallized from hexane, yield 11.2 g. of 5-acetyl-4 butyl-mercapto-1 ethyl-lI-I-pyrazolo[3,4-b]pyridine (81% M.P. 65

EXAMPLE 23 5-benzoyl-1-ethyl-4-phenylmercapto-lH- Py [3. ]py n (a) 5-benzoyl 1 ethyl-4-hydroxy-lH-pyrazolo[3,4-b] pyridine.222 g. of S-amino-l-ethylpyrazole (2 mol.) and 496 g. of ethoxymethylenebenzoylacetic acid ethyl ester (2 mol.) are heated with stirring to about until no more alcohol distills. The temperature is then raised to 240. The alcohol formed is distilled 01f in vacuo. After about one hour, the reaction is complete, the residue is cooled to room temperature and 500 ml. of methanol are added. S-benzyl-l-ethyl 4 hydroxy-lH-pyrazoloI3,4-b] pyridine crystallizes and is filtered ofi, yield 360 g. (67% M.P. 151.

(b) S-benzoyl 4 chloro-l-ethyl-lH-pyrazolo[3,4-b] pyridine.53.5 g. of S-benzoyl l ethyl-4-hydroxy lH- pyrazolo[3,4-b]pyridine (0.02 mol.) and ml. of phosphorus oxychloride are refluxed at 150 for 5 hours. The excess phosphorus halide is removed in vacuo and the residue is neutralized with saturated sodium bicarbonate solution. The pale yellow crystals of 5-benzoyl-f4-chlorol- 11 ethyl-1H-pyrazolo[3,4-b] pyridine are filtered off and recrystallized from ethyl acetate, yield 35 g. (61%), M.P. 140.

(c) S-benzoyl 1 ethyl-4-phenylmercapto-lH-pyrazolo[3,4-b]pyridine.--14.2 g. of -benzoyl-4-chloro-1- 12 added. 4-hydroxy-1- (4-picoly1) -1H-pyrazol0[3,4-b] pyridine-S-carboxylic acid ethyl ester crystallizes on standing, yield 33 g. (44%), M.P. 140.

(c) 4 hydroxy 1H pyrazolo[3,4 bjlpyridine 5- carboxylic acid ethyl ester.-3 g. of 4-hydroxy-1-(4-picethyl-lH-pyrazolo[3,4-b1pyridine (0.05 mol.) are treated 5 o1yl)-1H-pyrazo1o[3,4-b]pyridine-5-carboxylic acid ethyl 1n alcohol with 7.5 g. of potassium thiophenolate at reester (0.01 mol.) are dissolved in 20 ml. of acetic acid. flux temperature for 3 hours. The precipitated potassium 2,2, g. of selenium dioxide (0.02 mol.) and 2-3 drops of chloride is filtered off and the solvent is removed in vacuo. water are added. The mixture is refluxed for 30 minutes Recrystallization of the residue from ethyl acetate yields and then filtered off. 4-hydroxy-1H-pyrazolo[3,4-b1 ig. of S-benzoyl-1-ethyl-4-phenylmercapto-lH-pyrazolodine-S-carboxylic acidethyl ester precipitates oncooling. [3,4-b]pyr1d1ne (83%), M.P. 92-95. Recrystallization from acetic acid yields 1.8 g. (87%), 24 i 275. (d) 4 chloro 1H pyrazolo[3,4-b]pyridine 5 'c'ar- 4-butylmercapto-5-benzoyl;l;ethyl-lfl-pyrazolo 15 boxylic acid ethyl ester.4-hydroxy-lH-pyrazolo[3,4-b] lpy pyridine-S-carboxylic acid ethyl esteris treated with phos- 28.5 g. of 5-benzoyl-1-ethyl-4-chl0ro-H-I-pyrazolo[3,4- Phoms Oxychloride Example obfain b]pyridine (0.1 mol.) are added to a suspension of 11.2 lH-pyfazolo[3,4-b]pyrldlne-icafboxyllc acld ethyl F g. of sodium butylmercaptide in 50 ml. of anhydrous di- (6) 4 fathylfnercapto 1H PYraZOlOBA b]pyndme' oxane. The mixture is heated for 5 hours at 70. After {3 acid yl H'PY Q[ 4? this time, the precipitated sodium chloride is filtered ofi, b]pyndme5'carbox yhc and ethyl ester treated wli-h dioxane is removed in vacuo and the residue recrystalethylmercaptan as m M to obtam, l i lized from hexane, yield 28 g. of 4-butylmercapto-5-benp ry ]py y c acld ethyl zoyl-l-ethyl-l H-pyrazolo[3,4-b1pyridine (82%), M.P. ester- (f) 4 ethylmercapto 1H pyrazolo[3,4-b]pyrrd1ne'- The following compounds are prepared by the proce- 5'carboxyllc of Y P -PY dure of Examples 22, 23 or 24 by substituting the appro- ]py p- -ca acld F y estel: f priately substituted 5 1.4- h1 1 1 3 44, treated Wlth a solution of 2.3 g. of potassium hydroxide in pyridine and the appropriate mercaptan. 20 ml. of alcohol for 12 hours at The solvent is R: i v i I in.

-R N N R: R: 77 R4 R5 H CH CH H gm 811i 3 cHi-cHioH= H H G 1 CH! H 28.--'::.: H H CHa-CHg 0 CHs-CH: H 29...'.":'.: Q CHI CHF-(GHIM- 0 Q E 30.....1: CHO (CHI)2CH 2 CH: CH:

31..:::;- O s-CH: Q CHx-CHz- 0 CHg-GHr-GHz-CHP H 32 CEh-CH: H OH: 2 on. Q

EXAMPLE 33 distilled off, the residue is dissolved in 20 ml. of water 4-ethylmercapto-lH-pyrazolo[3,4-b1pyridine-5- N-butylcarboxamide (a) [[[1 (4 picolyl) 5 pyrazolyl]amino]methylene]malonic acid diethyl ester.--174 g. of 1-(4-picoly)-5- aminopyrazole and 216 g. of ethoxymethylene malonic acid diethyl ester are heated with stirring at 140, until the theoretical amount of alcohol has distilled off. The reaction mixture crystallizes on cooling. Recrystallization from ethyl acetate yields 220 g. of [[[1-(4-picolyl)-5- pyrazolyl] amino]methylene]malonic acid diethyl ester (65% MP.. 95-97.

(b) 4-hydroxy 1 (4 picolyl) 1H pyrazolo[3,4- b]pyridine-5-carboxylic acid ethyl ester.--86 g. of [[[1- (4-picolyl) 5 pyrazolyl]amino]methylene]malonic' acid diethyl ester (0.25 mol.) are heated at 240 for 15 minutes. The dark oil is cooled and 200 m1. of methanol are and acidified with some acetic acid. 4-ethylmercapto-1H- pyrazolo[3,4-b]pyridine-S-carboxylic acid solidifies and is recrystallized.

(g) 4 ethylmercapto 1H pyrazolo[3,4-b]pyridine- 5-N-butylcarboxamide.-2.1 g. of 4-,ethylmercapto-1H- pyrazolo[3,4b]pyridine-5-carboxylic acid is refluxed with 10 ml. of thionyl chloride for 5 hours. After this time, the excess thionyl chloride is removed in vacuo and to the residue are added 20 ml. of anhydrous benzene. Then 1.5 g. of n-butylamine are dropped slowly into the reaction mixture, which is stirred for 12 additional hours at room temperature. Subsequently, the solvent is distilled off and 4-ethylmercapto-1H-pyrazolo[3,4-b]pyridine-5 N butyl carboxamide crystallizes.

The following compounds are prepared by the procedure of Example 33 by substituting the appropriately substituted 4-hydroxy-1H-pyrazolo 3,4-b pyridine-S-car- 3. A compound as in claim 1 wherein R and R each is lower alkyl, R, is lower alkoxy, R and R each is hyro- /Rl Example Ra R1 R1 11 CHa-CHz- -N(C2H5)5 GHP -NHCH(CH:)2

CH3-CHP NH(CH );CH

GHQ-CHz-CHi-CHQ- -NHCH; EOHQzOH-CHz-CHz- NH-oHCHa H;(OHz)6- -N(C2H5)fl OH OH CH| --NH(CH2)|CH:

CH CE 43 H (CH:)2CH- N/ s 44 CH CH N s N-E 8- N s Nort,

46 H 0 CH CH P -N s N-CHz-CHz-OH 7 CH: CH:

What is claimed is: 45 gen an n is 0. 1. A compound of the formula 4. A compound as in claim 3 wherein each lower alkyl group is ethyl and the lower alkoxy group is ethoxy. R; 5. A compound as in claim 1 wherein R is ethyl, R (o)n and R each is methyl, R is ethoxy, R is hydrogen and wherein R is hydrogen, lower alkyl, phenyl, benzyl, cyclopentyl or cyclohexyl, R is hydrogen, methyl or phenyl, R is hydrogen only when n is 0, lower alkyl, phenyl or benzyl, R is hydroxy, lower alkoxy, lower alkyl, phenyl or the group wherein R and R each is hydrogen, lower alkyl or hydroXy-lower alkyl, R is hydrogen, lower alkyl or phenyl and n is 0, 1 or 2, and physiologically acceptable salts thereof.

2. A compound as in claim 1 wherein R is hydrogen or lower alkyl, R is hydrogen or methyl, R is hydrogen, R is hydroxy, lower alkoxy, lower alkyl, phenyl or lower alkylamino, R is hydrogen or methyl and n is 0 or 2.

n is 2.

6. A compound as in claim 1 wherein R is lower alkyl, R R and R each is hydrogen, R is lower alkoxy and n is 0. v

7. A compound as in claim 6 wherein the lower alkyl group is ethyl and the lower alkoxy group is ethoxy.

8. A compound as in claim 1 wherein R is ethyl, R R and R each is hydrogen, R is hydroxy and n is 0.

References Cited UNITED STATES PATENTS 3,629,271 12/1971 Hoehn 260-2955 B OTHER REFERENCES Lowy et al., An Introduction to Organic Chemistry," 6th ed., Wiley Publishers, p. 214, QD 253 L88 (1945).

Roberts et al.: Basic Principles of Organic Chemistry, Benjamin Publishers, pp. 750, 756 and 806 (1965) QB 251 R 58 0.2.

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

260243 B, 247.1, 268 BC, 293.6, 295.5 B; 424--246, 248, 250, 266, 267 

